4-Phenyl-1,3-benzodioxans

ABSTRACT

Substituted 2-aminomethyl-4-phenyl-1,3-benzodioxans and derivatives thereof have been found to possess valuable anticonvulsant and antiarrhythmia activity in mammals. For example, cis-6-chloro-2-methylaminomethyl-4-phenyl-1,3-benzodioxan hydrochloride possesses potent anticonvulsant activity while cis-2-isopropylaminomethyl-4-phenyl-1,3-benzodioxan hydrochloride has potent antiarrhythmia activity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of a co-pending application,Ser. No. 434,463, filed Jan. 1, 1974 now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel optionally substituted2-aminomethyl-4-phenyl-1,3-benzodioxans and derivatives thereof whichpossess valuable anticonvulsant and antiarrhythmia activity.

2. Description of the Prior Art

Searches in the patent and scientific literature did not reveal theexistence of any 2-aminoalkyl-4-phenyl-1,3-benzodioxans,4-phenyl-1,3-benzodioxan-2-carboxylic acids or4-phenyl-1,3-benzodioxan-2-carboxamides. The closest art found relatedto the isomeric 1,4-benzodioxan ring system.

A. V. Dauksas and A. Lastauksas, Biol. Aktiv. Soedin., 286 (1968); Chem.Abstr. 71, 124348e (1969), which article reported the compounds havingthe structure ##STR1## in which --NR¹ R² are --N(CH₃)₂ or N--(C₂ H₅)₂ aspossessing local anesthetic activity.

B. F. Leonard and J. Koo, Belg. Patent 613,214, July 30, 1962; Chem.Abstr., 57, 16629c (1962), which article reported the compounds havingthe structure ##STR2## as possessing sedative and tranquilizingactivity.

C. U.S. Pat. No. 3,484,448 reports the compounds having ##STR3## whereinR₁ represents H, OH, RCH₂, RCHOH, RCO, alkoxy of 1-5 carbon atoms, or--O--(CH₂)_(n) --NR'R'';

R₂ represents H, OH, CH₃, alkoxy of 1-5 carbon atoms, or --O--(CH₂)_(n)--NR'R'';

R₃ represents H or alkyl of 1-6 carbon atoms;

R₄ represents H, OH, CH₃ O, or together with R₂, methylenedioxy;

R represents H or CH₃ ;

n is 2 or 3 and

R'and R'', being the same or different,

represent alkyl of respectively 1-3 carbon atoms, or together with theN-atom, a 5- or 6-membered heterocyclic ring, and wherein the group--O--(CH₂)_(n) --NR'R'' has a total of 4-8 carbon atoms as possessingcholesterol-level-lowering activity.

SUMMARY OF THE INVENTION

Compounds having the formula ##STR4## in which X and Y are alike ordifferent and are H, F, Cl, Br, CF₃ or nitro, Z is a radical having theformula ##STR5## in which R⁶ is H, (lower)alkyl or phenyl, R¹ and R² arealike or different and each is H, lower alkyl, cycloloweralkyl or whentaken together with the nitrogen a heterocyclic ring having the formula##STR6## n is an integer of 1 to 4 inclusive; or a pharmaceuticallyacceptable acid addition salt thereof.

COMPLETE DISCLOSURE

Compounds having the formula ##STR7## in which X and Y are alike ordifferent and are H, F, Cl, Br, CF₃ or nitro, Z is a radical having theformula ##STR8## in which R⁶ is H, (lower)alkyl or phenyl, R¹ and R² arealike or different and each is H, lower alkyl, cycloloweralkyl or whentaken together with the nitrogen a heterocyclic ring having the formula##STR9## and n is an integer of 1 to 4 inclusive; or a pharmaceuticallyacceptable acid addition salt thereof have been found to possess usefulanticonvulsant and antiarrhythmia activity in mammals. The compounds arespecifically useful in the treatment of grand and petite malepileptic-like convulsions and are useful as therapeutic andprophylactic agents in the treatment of cardiac arrhythmia.

For the purpose of this disclosure, the terms lower alkyl,cycloloweralkyl and lower alkoxy are radicals containing 1 to 6 carbonatoms. The term "pharmaceutically acceptable acid addition salt"includes all those salts commonly employed in pharmaceuticals which areprepared by the reaction of an amine with a pharmaceutically acceptableacid. Such acids include, among others, acetic, hydrochloric, sulfuric,maleic, phosphoric, nitric, hydrobromic, ascorbic, malic and citricacid.

A preferred embodiment of the present invention is the compound havingthe formula ##STR10## in which X and Y are alike or different and are H,F, Cl, Br, CF₃ or nitro, Z is a radical having the formula ##STR11## inwhich R⁶ is H, (lower)alkyl or phenyl, R¹ and R² are alike or differentand each is H, lower alkyl, cyclolower alkyl or when taken together withthe nitrogen a heterocyclic ring having the formula ##STR12## and n isan integer of 1 to 4 inclusive; or a pharmaceutically acceptable acidaddition salt thereof.

Another preferred embodiment is a compound having the formula ##STR13##in which X and Y are alike or different and are H, F, Cl, Br, CF₃ ornitro, Z is a radical having the formula ##STR14## in which R⁶ is H,(lower)alkyl or phenyl, R¹ and R² are alike or different and each is H,lower alkyl, cycloloweralkyl or when taken together with the nitrogen aheterocyclic ring having the formula ##STR15## and n is an integer of 1to 4 inclusive; or a pharmaceutically acceptable acid addition saltthereof.

A more preferred embodiment is a compound of formula L¹ in which X and Yare alike or different and are H, F, Cl, Br, CF₃ or NO₂, and Z is aradical having the formula ##STR16## in which R⁶ is H, (lower)alkyl orphenyl, R¹ and R² are alike or different and each is H, lower alkyl,cycloloweralkyl or when taken together with the nitrogen a heterocyclicring having the formula ##STR17## and n is an integer of 1 to 4inclusive; or a pharmaceutically acceptable acid addition salt thereof.

A most preferred embodiment is the compound having the formula ##STR18##or the hydrochloride salt thereof.

A most preferred embodiment is the compound having the formula ##STR19##or the hydrochloride salt thereof.

A most preferred embodiment is the compound having the formula ##STR20##or the hydrochloride salt thereof.

A most preferred embodiment is the compound having the formula ##STR21##or the hydrochloride salt thereof.

A most preferred embodiment is the compound having the formula ##STR22##or the hydrochloride salt thereof.

A most preferred embodiment is the compound having the formula ##STR23##or a pharmaceutically acceptable acid addition salt thereof.

A most preferred embodiment is the compound having the formula ##STR24##or a pharmaceutically acceptable acid addition salt thereof.

Also a preferred embodiment is the essentially pure cis and transisomers of the compounds described supra.

The compounds of structure L and L¹ contain a dioxan ring and twoasymmetric carbon atoms and may thus exist as both geometrical andoptical isomers. Two geometrical isomers, in approximately equal ratios,were typically obtained by our synthetic sequence. These were readilyseparated by fractional crystallization of the acids (IV) or the amides(V) from a suitable solvent. Nitromethane or a mixture of CCl₄ andethanol-free CHCl₃ were preferred.

The structures of the geometric isomers were assigned unambiguously by100 MHz nmr. See example 1c for a detailed discussion. Of the fourpossible isomers VII through X, VII and IX were shown to be the onesobtained by our procedures, and are referred to as cis and trans,respectively. Although each of these isomers may exist as a racemicmixture, no attempt was made at this time to resolve these racemates.However, all such isomers are within the scope of this invention.##STR25##

Shown below is the sequence employed to synthesize the compounds L:##STR26##

Primary or secondary amines L could be methylated by theEschweiler-Clarke¹ procedure. This method was particularly advantageousin preparing amines with two different substituents: ##STR27## 1.M. L.Moore, Organic Reactions, 5, 301 (1949).

The compounds L likewise provided other amines through amidation andreduction: ##STR28##

Compounds with a halogen in the 6-position could be easily dehalogenatedcatalytically. This could be done in the presence of another halogenelsewhere in the molecule. ##STR29##

Compound III (X = 5-Cl, Y = H) has been prepared, in unspecified yield,with NaBH₄ as reducing agent. This method was found to be not amenableto scaleup. Toluene, and particularly dioxane, were preferred solventsin the condensation of III with glyoxylic acid. Diborane in THF smoothlyreduced the amides V to the amines I. Other common reducing agents(LiAlH₄, AlH₃) were ineffective.

The objectives of the present invention have been achieved, by theprovision according to the present invention of the process for thepreparation of the compound having the formula ##STR30## in which X andY are alike or different and are H, F, Cl, Br, CF₃ or nitro, Z is aradical having the formula ##STR31## in which R⁶ is H, (lower)alkyl orphenyl, R¹ and R² are alike or different and each is H, lower alkyl,cycloloweralkyl or when taken together with the nitrogen a heterocyclicring having the formula ##STR32## and n is an integer of 1 to 4inclusive; which process comprises the consecutive steps of

A. treating a compound having the formula ##STR33## with an amine havingthe formula ##STR34## in which R¹, R² and R⁶ are as defined above toproduce the compound having the formula ##STR35## in which Z is definedas above; and

B. treating a compound having the formula ##STR36## in which X, Y and Zare as defined above; with diborane in tetrahydrofuran, dioxane, diethylether and the like, but most preferably tetrahydrofuran, in a ratio of 1mole of compound XXXX to at least 3 moles of diborane and preferably ina ratio of 1 mole of XXXX to 4 to 8 moles of diborane, and mostpreferably in a ratio of 1 mole of XXXX to 5.5 moles of diborane, withrefluxing for at least 10 hours, and preferably 15 to 25 hours.

The compounds L and L¹ of the instant invention have been found to beeffective agents in the prevention of tonic convulsions and thetherapeutic and prophylactic treatment of cardiac arrhythmia.

Table I illustrates the results obtained on four compounds; e.g.,BL-3069 (1B); BL-3168 (8B); BL-3396 (22B); and BL-3681A (28B) ascompared to 4 reference agents in the control of convulsions.

                                      Table I                                     __________________________________________________________________________    Anticonvulsant Profile of BL-3069, BL-3168, BL-3396, BL-3681 and              Reference Agents in the                                                       Mouse and Rat                                                                                         ED50, mg/kg po.sup.1                                              Maximal Electroshock.sup.2                                                                Audiogenic Seizure.sup.3                                                                  Pentylenetetrazole                                                                        LD50.sup.6                    Compound    Mouse Rat   Mouse       Mouse   Rat Mouse                         __________________________________________________________________________    BL-3069 (1B)                                                                              25    >20   --          12.sup.4                                                                          --   >40.sup.5                                                                        300                           BL-3168 (8B)                                                                              10    15    2.5         5    >50.sup.5                                                                        >40 300                           BL-3396 (22B)                                                                             10    10    2.5         3   >50 >40 400                           BL-3681A (28B)                                                                            12    15    10          12  >50 >40 300                           Diphenylhydantoin Na                                                                      10    30    10          20  >50 40  540                           Diazepam     6    10    0.5         2    2   5  1400                          Phenobarbital Na                                                                          10     8    2.5         8   15  20  265                           Trimethadione                                                                             >400  300   150         200 400 100 2170                          __________________________________________________________________________     .sup.1 Test compounds including reference agents were administered orally     either as water solutions or as fine suspensions in Tween by gastric          intubation 60 min prior to the test. There were at least 3 animals per        dose.                                                                         .sup.2 Maximal Electroshock Test - Animals were subjected to an 80mA shoc     of 0.5 sec duration by a means of corneal electrodes using the specially      designed apparatus manufactured by Wahlquist Instrument Co. Prevention of     tonic extension by hind limbs was used as a criterion for drug effect.        .sup.3 Audiogenic Seizures - Mice, which were genetically bred for the        susceptability to sound induced seizures (O'Grady Farms) were placed into     the sound attenuated box and exposed to a 120 sec sound stimulus of 85 db     and 10,000 c/sec frequincy. Prevention of tonic extension of hind limbs       was used as a criterion for drug effect.                                      .sup.4 Pentylenetetrazol Infusion (Mouse) - The procedure originally          described by Orloff, M. H. et al., Proc. Soc. Exp. Biol. 70:254 (1949) an     adopted by our laboratories was used.                                         .sup.5 Pentylenetetrazol Standard Dose - Animals were challenged with a       standard dose of pentylenetetrazol (125 mg/kg ip) following pretreatment      with a test compound. Prevention of lethality was used as criterion for       drug effect.                                                                  .sup.6 Acute Toxicity (Mouse) - Animals were observed for a period of 24      hours following drug administration.                                     

As can be seen from the table, BL-3069, BL-3168, BL-3396 and BL-3681Awere effective blocking agents of tonic convulsions induced by maximalelectroshock and audiogenic seizures, while they proved practicallyineffective against pentylenetetrazole.

In the latter procedure, they merely antagonized the tonic convulsantcomponent of the stimulatory pattern while they were ineffective againstclonic convulsions and death (see footnotes 4 and 5 in Table I,respectively). Thus, it is apparent that they mimicked diphenylhydantoinwith respect to the activity profile. The known pentylenetetrazolantagonisits (diazepam, trimethadone and phenobarbital) were able toantagonize all the excitatory signs induced by pentylenetetrazol, i.e.,clonic and tonic convulsions and lethality, however, this was not thecase with the BL-compounds.

Thus, it can be concluded that the compounds L and L¹ can be classifiedas diphenylhydantoin-like compounds on the basis of the laboratoryresults.

The dose of the compounds L and L¹ in man is 25 to 500 mg three to fourtimes a day depending upon the severity of the grand mal and/or petitemal seizures and the compound L so used. The patient must be titratedwith the particular compound until a convulsion suppressing does isfound. The compounds can be used as therapeutic or prophylactic agents.

The compounds were also tested in dogs for their reversion activity inouabain-induced arrhythmia.

Anesthetized dogs were used for the production of ouabain-inducedventricular arrhythmias. The arrhythmia consisted of a nodal orventricular tachycardia. The procedure used to establish the arrhythmiaas well as the criteria employed to determine anti-arrhythmic activitygenerally was that employed by Lucchesi et al. ¹

Anti-arrhythmic activity of the compounds was determined by rapidintravenous injection and compared to lidocaine, disopyramide andaprindine The average prolonged reversion doses are shown below:

                                      TABLE I                                     __________________________________________________________________________    Effect of Various Substituted Phenylbenzodioxans on Ouabain-Induced           Cardiac Arrhythmias in the Anesthetized Dog                                   __________________________________________________________________________     ##STR37##                                                                    Compound                                                                      BL No. X  CY  R            Isomer                                                                            I. V. Reverting Dose, mg/kg.sup.a              __________________________________________________________________________    3168   Cl CH.sub.2                                                                          CH.sub.3 . HCl                                                                             cis >10 (N=1)                                                                     Decrease in mean aortic                                                       pressure of 20 mmHg.                           4093   Cl CO  CH.sub.3 . HCl                                                                             cis >10 (N=1)                                      3100   Cl CH.sub.2                                                                          CH.sub.3     trans                                                                             >10 (N=1)                                                                     Decrease in mean aortic                                                       pressure of 50 mmHg.                           3167   Cl CO  CH.sub.3     trans                                                                             >10 (N=1)                                      3418   H  CH.sub.2                                                                          CH(CH.sub.3).sub.2 . HCl                                                                   cis 3-5 (N=2)                                      3379   Cl CH.sub.2                                                                          CH(CH.sub.3).sub.2 . HCl                                                                   trans                                                                             >10 (N=1)                                      3374   Cl CO  CH(CH.sub.3).sub.2                                                                         trans                                                                             >10 (N=1)                                      3394   H  CH.sub.2                                                                          CH(CH.sub.3).sub.2 . HCl                                                                   trans                                                                             ˜10 (N=1)                                                               Accompanied by a pro-                                                         gressive fall in aortic                                                       blood pressure.                                4981A  H  CO  (CH.sub.2).sub.3N(CH.sub.3).sub.2 . HCl                                                    cis >10 (N=2)                                      4932A  Cl CO  (CH.sub.2).sub.3N(CH.sub.3).sub.2 . HCl                                                    trans                                                                             Transient reversion at                                                        10 mg/kg, transient 50                                                        mmHg fall in aortic blood                                                     pressure (N=2).                                4971A  Cl CO  (CH.sub.2).sub.3N(CH.sub.3).sub.2 . HCl                                                    cis 5 (N=3)                                                                       No appreciable effect on                                                      aortic blood pressure.                         Lidocaine                      6.4 ± 1.4 (N=8)                             Disopyramide                   4.5 ± 1.3 (N=6)                             Aprindine                      2.46 ± 0.83 (N=5)                           __________________________________________________________________________     N=Number of dogs.                                                             .sup.a IV ED100 refers to the dose of drug resulting in total reversion t     a normal sinoatrial rhythm for greater than 30 mins., unless otherwise        noted.                                                                   

The compounds of the present invention are useful in the treatment ofcaridac arrhythmia in mammals, including man, as prophylactic ortherapeutic agents in doses in the range of 0.25 mg. to 3.0 mg./kg. upto 3 or 4 times a day.

PREFERRED EMBODIMENTS EXAMPLE 1 Cis-andTrans-6-Chloro-4-Phenyl-1,3-Benzodioxan-2-Carboxylic Acids ##STR38## a.5-Chloro-2-hydroxybenzhydrol²

5-Chloro-2-hydroxybenzophenone (100.0 g, 0.429 mole) was dissolved withstirring, under anhydrous conditions, in 1 liter of anhydrous THF(tetrahydrofuran) contained in a 5 1. flask. The flask was immersed inan ice-water bath, the solution was stirred vigorously, and 450 ml (0.45mole) of diborane in THF soln (1M as BH₃) was immediately added from adropping funnel as rapidly as maintaining control of the reaction wouldallow; about 4 minutes was required. Foaming occurred and the color ofthe reaction mixture deepened, then lightened. After addition, thecolorless solution was stirred in the cooling bath for 15 minutes andwas then poured slowly, cautiously, and with good stirring onto amixture of cracked ice and 700 ml of 5% HC1 soln.

The insoluble material was extracted out with 3 portions of ether; thecombined extracts were washed with dilute NaHCO₃ soln (2 portions),water (1 portion) and saturated brine (1 portion) and dried overanhydrous MgSO₄. Evaporation of the solvents gave an oil which was takenup in hot cyclohexane; the solvent was evaporated and the residue wasstripped in vacuum. The oil thus obtained was dissolved i 1200 ml of hotcyclohexane; the solution was filtered, seeded, and allowed to stand atroom temperature.

The solid was filtered, washed with cyclohexane, and air-dried. Lightcream-colored crystals, mp 93°-95°, were obtained. The yield was 64.5 g(62%).

b. cis-and trans-6-Chloro-4-phenyl-1,3-benzodioxan-2 -carboxylic acids

A solution of 118 g (0.525 mole) of 5-chloro-2-hydroxybenzhydrol, 83 g(0.822-0.902 mole) of glyoxylic acid hydrate³, and 0.7 g ofp-toluene-sulfonic acid hydrate in 1000 ml of dioxane was stirred andheated to boiling. Solvent was distilled and fresh dioxane was added tomaintain the pot volume at ca. 1 1. Distillation was continued for 12hrs.; a total of 3.7 1. of distillate was collected. The reactionmixture then cooled to room temperature over a period of 8 hrs.

The reaction mixture was stripped of dioxane in vacuum; the residue wasdissolved in ether and the solution was washed with two portions ofwater. The ether solution was then extracted with 6 portions of diluteNaHCO₂ solution and discarded. The combined NaHCO₃ extracts wereacidified with conc. HCl and the insoluble material was extracted outwith ether. The ether solution was washed with water (3 portions) andsaturated brine (2 portions) and dried over anhydrous Na₂ SO₄.Evaporation of the solvent gave 140 g (92%) of a solid mixture of acids.

This material was combined with 77g from a pervious run (total, 217 g)and the mixture was stirred and boiled with 500 ml of CCl₄ and 1800 mlalcohol-free CHCl₃. The insoluble material was filtered, washed with two250 ml portions of boiling CHCl₃, and dried in vacuum to yield 20.2 g ofpure, colorless cis-6-chloro-4-phenyl-1,3-benzodioxan-2-carboxylic acid,mp 191°-193°. Upon 12 hr's standing at room temperature, the filtratedeposited a solid; this was filtered, washed with CCl₄, and dried toprovide 62.7 g of less pure cis-acid. The mother liquor was reserved forrecovery of the trans-isomer. The impure cis-acid was recrystallizedfrom nitromethane to give an additional 37.6 g of cis-acid, m.p.192°-193°. The total yield was 56.8 g (24.5% or 49% of availablecis-isomer). Nuclear Magnetic Resonance Spectra [NMR (CDCl₃ -DMSO)],dδ6.62 (d, 1H, C(5)H, cis; 5.65 ppm (s, 1H, C(2)H, cis).

Anal. Calc'd for C₁₅ H₁₁ ClO₄ : C, 61.98; H, 3.81; Cl, 12.20. Found: C,61.82; H, 3.74; C1, 12.13.

Upon standing at room temperature, the mother liquor and washings fromisolation of the cis-isomer deposited additional solid. This wasfiltered and washed with CCl₄ to give 28.6 g of puretrans-6-chloro-4-phenyl-1,3-benzodioxan-2-carboxylic acid; m.p.153°-154.5°. The filtrate provided a second crop, 12.3 g, m.p.153°-154°. The mother liquor was discarded. The total yield oftrans-acid was 40.9 (17.3% or 34.6% of available trans-isomer). NMR(CDCl₃ -DMSO), δ6.85 (d, 1H, C(5)H, trans); 5.42 ppm (s, 1H, C(2)H,trans).

Anal. Calc'd for C₁₅ H₁₁ ClO₄ : C, 61.98; H, 3.81; Cl, 12.20. Found: C,62.25; H, 4.08; Cl, 12.14.

c. Methyl esters and assignment of structures

1. cis-Methyl 6-chloro-4-phenyl-1,3-benzodioxan-2-carboxylate

To an ether solution ofcis-6-chloro-4-phenyl-1,3-benzodioxan-2-carboxylic acid (2.14 g, 7.36mmoles), chilled in an ice bath, was added an ethereal solution ofdiazomethane until the yellow color of the diazomethane was no longerdischarged. The solution was stirred in the ice bath for 10 minutes atroom temp. for 10 minutes, and finally at 35° for 15 minutes. The ethersolution was washed with dil.NaHCO₃ solution (2 portions), water (2portions), and saturated brine (1 portion), and dried over anhydrous Na₂SO₄. The solvent was evaporated to yield a solid which wasrecrystallized from benzene-Skellysolve B (essentially n-hexane). Theyield was 1.71 g (76%); m.p. 129.5°-131°. NMR (CDCl₃), β6.6 (d, 1H,C(5)H, cis); 5.65 ppm (s, 1H, C(2)H, cis).

Anal. Calc'd. for C₁₆ H₁₃ ClO₄ : C, 63.07; H, 4.30; Ca, 11.63. Found: C,63.24; H, 4.59; Cl, 11.79.

2. trans-Methyl 6-chloro-4-phenyl-1,3-benzodioxan-2-carboxylate.

A similar procedure to that described in part 1 above, utilizing 2.08 g(7.14 mmoles) of trans-6-chloro-4-phenyl-1,3-benzodioxan-2-carboxylicacid, provided 1.79 g (82%) of trans-ester; m.p. 103.5-106.5%. NMR(CDCl₃), δ6.85 (d, 1H, C(5)H, trans); 5.5 ppm (s, 1H, C(2)H, trans)

Anal. Calc'd. for C₁₆ H₁₃ ClO₄ : C, 63.07; H, H, 4.30; Cl, 11.63. Found:C, 63.40; H, 4.60; Cl, 11.31.

3. Assignment of structures ##STR39##

The structures of the two methyl esters were assigned unambiguously onthe basis of their 100 MHz nmr spectra in CDCl₃ soln.

a. The isomer from 1 was shown to have the cis-structure A by:

1. The appearance of H_(a) as a doublet centered at 6.6δ (upfield fromH_(a) in 2), indicating that the monsubstituted phenyl was equatorial.This conformation was also indicated by appearance of H_(c) as a singletat 5.7δ (downfield from H_(c) in 2).

2. Demonstration of a nuclear Overhauser effect between H_(b) and H_(c)upon double resonance, indicating a cis-diaxial relationship.

b. The isomer from 2 was shown to have the trans-structure B by:

1. The appearance of H_(a) as a doublet centered at 6.85δ (downfieldfrom H_(a) in 1), indicating that the monosubstituted phenyl was axial.This conformation was also indicated by appearance of H_(c) as a singletat 5.5δ (upfield from H_(c) in 1), showing proximity of the phenyl.

2. Absence of a nuclear Overhauser effect between H_(b) and H_(c).

EXAMPLE 2 cis-and trans-6-Chloro-4-(4-chlorophenyl)-1,3-benzodioxan2-carboxylic acids

a. 4',5-Dichloro-2-hydroxybenzhydrol

The procedure described in example 1a was followed, using 25.0 g (93.5mmoles) of 4',5-dichloro-2-hydroxybenzophenone⁴ and 100 ml (100 mmoles)of diborane in THF solution (1M as BH₃). Workup gave an oil which wascrystallized from 450 ml of cyclohexane to yield a colorless solid; m.p.106°-107°. A second crop was obtained, m.p. 105°-106.5°. The total yieldwas 21.5 g (85%).

Anal. Calc'd. for C₁₃ H₁₀ Cl₂ O₂ : C, 58.02; H, 3.75; Cl, 26.35. Found:C, 57.70; H, 3.70; Cl, 26.26.

b. cis-andtrans-6-Chloro-4-(4-chlorophenyl)-1,3-benzodioxan-2-carboxylic acids

4',5-Dichloro-2-hydroxybenzyhydrol (30.0 g, 0.116 mole) was reacted with25.0 g (0.25-0.30 mole) of glyoxylic acid hydrate and 0.2 g ofp-toluene-sulfonic acid hydrate in 600 ml of dioxane as described inExample 1b. Upon workup, 34.7 g of mixed acids was obtained (92%conversion). The mixture was dissolved hot in 300 ml of CCl₄ and 300 mlof alcohol-free CHCl₃. The solution was filtered, seeded, and stood atroom temperature and then at 0°. The solid was filtered and washed withcold CCl₄ to give 8.5 g of almost pure cis-acid; mp 175°-178°. Themother liquor was reserved for recovery of the trans-isomer. The solidwas recrystallized from CCl₄ --CHCl₃ to give 4.05 g of pure cis-acid;m.p. 183°-184°. A second crop (0.94 g) was obtained; mp 182.5°-183.5°.

The first mother liquor was evaporated and the residue was dissolved in150 ml of hot CCl₄ and crystallized at room temp. The solid thusobtained was filtered and recrystallized from CCl₄ --CHCl₃ ; 5.59 g ofalmost pure trans-acid was obtained; m.p. 150.5°-151.5°. The motherliquor, upon standing, deposited a solid which upon recrystallizationfrom CCl₄ --CHCl₃ provided an additional 2.4 g of pure cis-acid; m.p.180°-181.5°. The trans-isomer was recrystallized from CHCl₃ --CCl₄ andagain from CH₃ NO₂ to give 3.05 g of pure trans-acid as a white powder;mp 159°-161°.

The yields were: cis, 17.3% (35% of available isomer); trans, 8.1% (16%of available isomer). NMR (CDCl₃ -DMSO), δ 6.62 (d, 1H, C(5)H, cis);5.66 (s, 1H, C(2)H, cis); 6.82 (d, 1H, C(5)H, trans); 5.44 ppm (s, 1H,C(2)H, trans).

Anal. Calc'd. for C₁₅ H₁₀ Cl₂ O₄ : C, 55.41; H, 3.10; Cl, 21.81. Found(cis): C, 55.23; H, 3.15; Cl, 22.09. Found (trans): C, 55.39; H, 3.18;Cl, 22.10.

EXAMPLE 3 cis-andtrans-6-Chloro-4-(2-fluorophenyl)-1,3-benzodioxan-2-carboxylic acids

a. 5-Chloro-2'-fluoro-2-hydroxybenzophenone

Anhydrous AlCl₃ (160 g, 1.2 moles) was heated to 95° in an oil bath and153 g (1.2 moles) of 4-chlorophenol and 190 g (1.2 moles) of2-fluorobenzoyl chloride were added rapidly and simultaneously withstirring. Fumes were evolved and the reaction mixture liquified. Afteraddition was completed, the mixture solidified. The bath temperature wasraised to 145°; the reaction mixture again liquified and HCl wascopiously evolved. The bath temperature was then raised to 195° and heldfor 25 minutes. The reaction mixture cooled slowly to room temperature;a glass was obtained.

The mixture was decomposed by the slow cautious addition of 6N HCl. Theproduct was extracted out with CHCl₃. The combined extracts were washedwell with H₂ O, dried over anhydrous Na₂ SO₄, and evaporated. The solidthus obtained was recrystallized three times from MeOH to give 209.7 g(70%) of yellowish crystals; mp 76°-80.5°.

Anal. Calc'd. for C₁₃ H₈ ClFO₂ : C, 62.29; H, 3.22; Cl, 14.15. Found: C,62.00; H, 3.40; Cl, 14.16.

b. 5-Chloro-2'-fluoro-2-hydroxybenzhydrol

Under anhydrous conditions, a stirred solution of 25.0 g (99.5 mmoles)of 5-chloro-2'-fluoro-2-hydroxybenzophenone in 250 ml of anhydrous THFwas heated to reflux. The heat source was removed and 115 ml (115mmoles) of a solution (1M in BH₃) of diborane in THF was added rapidlyfrom a dropping funnel; foaming and some refluxing occurred. Afteraddition, external heating was resumed and refluxing was continued for 5min. A few minutes after heating was resumed, the yellow color of theketone was discharged. The colorless solution was cooled to roomtemperature and worked up as described in Example 1a. An oil wasobtained in quantitative yield which was used without furtherpurification in the next step.

In one instance, crystallization of the material from cyclohexaneoccurred; colorless solid, mp 64°-65°. This was not reproducible.

Anal. Calc'd. for C₁₃ H₁₀ ClFO₂ : C, 61.79; H, 3.99; Cl, 14.03. Found:C, 61.92; H, 3.99; Cl, 13.98.

c. cis-and trans-6-Chloro-4-(2-fluorophenyl)1,3-benzodioxan-2-carboxylic acids

Crude 5-chloro-2'-fluoro-2-hydroxybenzhydrol (0.199 mole, assumingquantitative conversion), 38.4 g (0.379-0.416 mole) of glyoxylic acidhydrate, and 0.51 g of p-toluenesolfonic acid hydrate were reacted in200 ml of dioxane as described in Example 1b. Distillation time was 6hrs. and distillate volume was 3200 ml. Workup provided 38.5 g (62.5%overall conversion) of mixed acids as a reddish resin.

The mixture was dissolved in 100 ml of hot CCl₄, scratched, and storedat -15°. The solid (19.2 g) was filtered, washed with cold CCl₄, andrecrystallized twice from CH₃ NO₂ to yield 4.72 g of pure cis-acid; mp170°-171° (bubbling), as a colorless powder. The second CH₃ NO₂ motherliquor was evaporated and the residue was recrystallized twice from CH₃NO₂ to yield pure trans-acid, colorless powder, 1.71 g., mp 158°-160°.

The CCl₄ mother liquor was evaporated to give a second crop. This wasrecrystallized from CCl₄ and then from CH₃ NO₂ to provide an additional1.89 g of pure cis-acid; mp 170.5°-172° (bubbling).

The yields were: cis, 10.7% overall (34% recovery of available isomer);trans, 2.8% overall (8.9% recovery of available isomer).

NMR (CDCl₃ -DMSO), δ6.67 (d, 1H, C(5)H, cis); 6.46 (s, 1H, C(4)H, cis);5.66 (s, 1H, C(2)H, cis); 6.79 (d, 1H, C(5)H, trans); 6.37 (s, 1H,C(4)H, trans); 5.50 ppm (s, 1H, C(2)H, trans).

Anal. Calc'd. for C₁₅ H₁₀ ClFO₄ : C, 58.36; H, 3.27; Cl, 11.49. Found(cis): C, 58.66; H, 3.49; Cl, 11.79. Found (trans): C, 58.21; H, 3.37;Cl, 11.69.

EXAMPLE 4 cis-and trans-4-Phenyl-6-nitro-1,3-benzodioxan-2-carboxylicacids

a. 2-Hydroxy-5-nitrobenzophenone

The literature preparation⁵ of this material was inconvenient and theyields were very low. The following procedure was found to besatisfactory.

2-Chloro-5-nitrobenzophenone (50.0g, 0.191 mole) was dissolved in 500 mlof ethylene glycol at about 100°. Water (20 ml) and 16.06 g (0.286 mole)of KOH pellets were added and the mixture was stirred and heated underreflux in an oil bath at 150°-160° (internal temp., 135°) for 6 hours.

The dark solution was cooled and poured into 2 l of cold water. themixture was made strongly basic with 40% KOH solution and stirred for ashort time. The solid material was then filtered and the filter cake waswashed well with H₂ O. The filtrate was acidified with conc. HCl to givea solid material which was extracted out with CH₂ Cl₂. The solvent wasevaporated and the solid recrystallized from 95% EtOH to give 7.81 g(17%) of 2-hydroxy-5-nitrobenzophenone; mp 127°-129°.

The solid first obtained was dried and recrystallized from 95% EtOH toyield 35.6 g (65%) of 2-(2-hydroxyethoxy)-5-nitrobenzophenone; mp124.5°-126°. Conversion to total products was thus 82%.

Anal. Calc'd. for C₁₅ H₁₃ NO₅ : C, 62.71; H, 4.56; N, 4.88. Found: C,62.51; H, 4.40; N, 4.88.

a solution of 2-(2-hydroxyethoxy)-5-nitrobenzophenone (19.08 g, 66.5mmoles) in 475 ml of anhydrous CH₂ Cl₂ was added all at once to asolution of 19 ml (50.2 g, 200 mmoles) of boron tribromide in 200 ml ofanhydrous CH₂ Cl₂. The solution became orange in color and some heatevolution was noted. The flask was stoppered and the reaction mixturestood at room temp for 18 hours.

The solution was poured into excess ice water; the mixture was stirredwell and the layers were separated. The aqueous was extracted with twoportions of CH₂ Cl₂ and discarded. The combined organic solutions wereevaporated and the solid residue was recrystallized from 95% EtOH. Theyield of 2-hydroxy-5-nitrobenzophenone was 15.18 g (94%), mp 128°-129°.The total yield of product was thus 78%.

b. cis-and-trans-4-Phenyl-6-nitro-1,3-benzodioxan-2-carboxylic acids

2-Hydroxy-5-nitrobenzophenone was reduced to 2-hydroxy-5-nitrobenzhydrolessentially as described in Example 1a⁶. Following addition of thediborane, the solution was stirred and refluxed for 10 minutes. Workupgave the diol as a brown resin, still containing some THF. This materialwas used directly for preparation of the acid. Quantities of reactantswere calculated assuming 100% yield.

Crude 2-hydroxy-5-nitrobenzhydrol (0.247 mole) was condensed with 48.0 g(0.475-0.522 mole) of glyoxylic acid hydrate in 200 ml of dioxane and0.54 g of p-toluenesolfonic acid hydrate as described in Example 1b.Distillation time was 3 hours and 1880 ml of distillate was collected.The usual workup was performed. During filtration of the ether solutionof mixed acids from the MgSO₄ dessicant, a solid suddenly separated.Repeated washings with CH₂ Cl₂ cleared the solid from both the filterand the filtrate. The filtrate was evaporated to yield a dark resinwhich was dissolved in 500 ml of ether. The solution was seeded;immediate separation of a crystalline solid began. The mixture wasallowed to crystallize at room temperature and was then stored at 0°.

Filtration, washing with 50 ml of cold (--15°) ether, and drying (110°,briefly) gave 16.9 g of pure cis-acid as light yellowish needles; mp193°-195°. The mother liquor was evaporated to 100 ml, seeded, andstored at -15°, impure trans-acid (12.1 g) was obtained. This wasrecrystallized from 130 ml of CH₃ NO₂ to give 7.86 g of pure trans-acid;mp 188.5°-190°. The yields were: cis, 22.8% (45% of available isomer;trans, 10.6% (21.2% of available isomer).

Nmr (CDCl₃ -DMSO), δ7.51 (d, 1H, C(5)H, cis); 5.77 (s, 1H, C(2)H, cis);7.75 (d, 1H, C(5)H, trans); 5.58 ppm (s, 1H, C(2)H, trans).

Anal. Calc'd. for C₁₅ H₁₁ NO₆ : C, 59.80; H, 3.68; N, 4.65. Found (cis):C, 59.70; H, 3.84; N, 4.65. Found (trans): C, 59.70; H, 3.61; N, 4.63.

EXAMPLE 5 cis-6-Chloro-2-methylaminomethyl-4-phenyl-1,3-benzodioxanhydrochloride. BL-3186

a. cis-6-Chloro-N-methyl-4-phenyl-1,3-benzodioxan-2-carboxamide

To a stirred slurry, under nitrogen, of 8.2 g (28.1 mmoles) ofcis-6-chloro-4-phenyl-1,3-benzodioxan-2-carboxylic acid in 300 ml ofanhydrous benzene was added slowly 33g (280 mmoles) of thionyl chloride.A few drops of anhydrous DMF (dimethylformamide) was added and themixture was stirred under reflux for 3 hours.

Solution was attained at the boil. The solvent and excess SOCl₂ wereremoved under reduced pressure; the residue was flashed down with twoportions of benzene to remove traces of SOCl₂.

The solid acid chloride was dissolved in CH₂ Cl₂ and the solution wassaturated with anhydrous CH₃ NH₂. A copious precipitate was observed.The mixture was stirred for 15 minutes, saturated again with CH₃ NH₂,stirred for 1 hour, saturated a third time with CH₃ NH₂, and finallystirred overnight at room temperature.

The mixture was washed with water (four portions), saturated NaHCO₃solution (two portions), and saturated brine (one portion) and driedover anhydrous Na₂ SO₄. The solvent was evaporated and the residualsolid was recrystallized from absolute ethanol to give 5.97 g ofcolorless crystals; mp 169°-170°. A second crop was obtained to raisethe yield to 7.67 g (90%).

Anal. Calc'd. for C₁₆ H₁₄ ClNO: C, 63.27; H, H, 4.64; N, 4.61; Cl,11.67. Found: C, 63.30; H, 4.72; N, 4.63; Cl, 11.27.

b. cis-6-Chloro-2-methylaminomethyl-4-phenyl-1,3-benzodioxanhydrochloride

To a stirred solution, under nitrogen, of 8.0 g (26.4 mmoles) ofcis-6-chloro-N-methyl-4-phenyl-1,3-benzodioxan-2-carboxamide was addeddropwise, at room temperature, 150 ml (150 mmoles) of diborane (1M asBH₃) in THF solution. After addition was complete, the solution wasstirred and refluxed for 21 hours.

The solution was cooled in an ice bath the 125 ml of 5% HCL was addeddropwise over a period of 1 hour. The solution was then evaporated underreduced pressure. The residue was partitioned between ether and dil.NaOH solution. The layers were separated and the alkaline aqueoussolution was extracted with ether. The extracts were combined and washedwith saturated NaHCO₃ solution, water and saturated brine and dried overanhydrous K₂ CO₃.

The solution was concentrated and the salt was formed with HCl gas. Themixture was evaporated and the residual solid was dissolved in hotabsolute EtOH. The solution was filtered, reheated, and ether was addedto cloudiness at the boil. The product crystallized at room temp to give6.52 g of colorless solid; mp 242.5°-243°. The mother liquor wasevaporated and the residue was recrystallized in a like manner to yielda second crop, 2.25 g; mp 239°-240°.

The total yield was 98%. Anal. Calc'd. for C₁₆ H₁₆ ClNO₂.HCl: C, 58.91;H, 5.25; N, 4.29. Found: C, 58.94; H, 5.34; N, 4.09.

EXAMPLE 6 cis-6-Chloro-4-phenyl-2-(2-propylaminomethyl)-1,3-benzodioxanhydrochloride. BL-3396

a. cis-6-Chloro-4-phenyl-N-(2-propyl)-1,3-benzodioxan-2-carboxamide

To a solution at room temperature of 6.0 g (20.6 mmoles) ofcis-6-chloro-4-phenyl-1,3-benzodioxan-2-carboxylic acid and ca. 1 ml ofanhydrous DMF (dimethylformamide) in 300 ml of anhydrous CH₂ Cl₂ wasadded dropwise a solution of 8.95 ml (123.6 mmoles) of thionyl chloridein 50 ml of anhydrous CH₂ Cl₂. After addition, the solution was stirredand refluxed for 2.5 hours. The solvent and excess SOCl₂ were thenremoved under reduced pressure and the residue was flashed down twicewith anhydrous benzene to remove traces of SOCl₂. The residue wasredissolved in ca. 200 ml of CH₂ Cl₂ and a solution of 7.7 g (130mmoles) of 2-aminopropane in ca. 50 ml of CH₂ Cl₂ was added. Heat wasevolved. The solution was mixed well and allowed to stand in a stopperedflask at room temperature for 65 hours.

The solution was washed with 5% HCl solution (four portions), water (twoportions), and saturated brine (two portions) and was dried overanhydrous Na₂ SO₄. The solvent was evaporated to yield 4.5 g (99%) ofamide. A sample was recrystallized from abs EtOH, mp 185°-186°.

Anal. Calc'd. for C₁₈ H₁₈ NO₃ Cl: C, 65.15; H, 5.47; N, 4.22. Found: C,65.02; H, 5.50; N, 4.29.

b. cis-6-Chloro-4-phenyl-2-(2-propylaminomethyl)-1,3-benzodioxanhydrochloride

A solution ofcis-6-chloro-4-phenyl-N-(2-propyl)-1,3-benzodioxan-2-carboxamide (6.6 g,20.0 mmoles) in 400 ml of anhydrous THF was treated with 80 ml (80mmoles) of diborane in THF solution (1M as BH₃) and the reaction mixturewas worked up essentially as described in Example 5b. The oily amine wasconverted to the hydrochloride in anhydrous ether; 7.4 g of colorlesspowder was obtained. Recrystallization from absolute EtOH gave 5.96 g(84%) of colorless crystals; mp 224.5°-225.5°.

Anal. Calc'd. for C₁₈ H₂₀ NO₂.HCl: C, 61.02; H, 5.98; N, 3.95. Found: C,61.20; H, 6.09; N, 4.05.

EXAMPLE 7trans-6-Chloro-4-(2-fluorophenyl)-2-(2-propylaminomethyl)-1,3-benzodioxanhydrochloride. BL-3681A

a.trans-6-Chloro-4-(2-fluorophenyl)-N-(2-propyl)-1,3-benzodioxan-2-carboxamide

A solution of 3.38 g (10.9 mmoles) oftrans-6-chloro-4-(2-fluorophenyl)-1,3-benzodioxan-2-carboxylic acid,10.0 ml (16.4 g, 137 mmoles) of thionyl chloride, and 5 drops ofanhydrous DMF in 200 ml of anhydrous Ch₂ Cl₂ was refluxed for 2 hours;the solvent and excess SOCl₂ were removed under reduced pressure and theresidue was flashed down with 3 portions of anhydrous benzene to removetraces of SOCl₂. The acid chloride was redissolved in 100 ml ofanhydrous CH₂ Cl₂ and 5.57 ml (3.86 g, 65.4 mmoles) of 2-aminopropanewas added all at once; heat was evolved. The reaction mixture stood in astoppered flask for 16 hours.

The reaction mixture was evaporated. The residue was partitioned betweenether and water and the mixture was worked up as described in Example6a. The solid amide obtained was recrystallized from EtOH--H₂ O to give3.40 g (89%) of colorless needles; mp 125°-126°.

Anal. Calc'd. for C₁₈ H₁₇ ClFNO₃ : C, 61.80; H, 4.90; N, 4.01; Cl,10.14. Found: C, 61.83; H, 5.20; N, 4.05; Cl, 10.30.

b.trans-6-Chloro-4-(2-fluorophenyl-2-(2-propylaminomethyl-1,3-benzodioxanhydrochloride

The reduction was performed essentially as described in Example 5b,employing 2.86 g (8.18 mmoles) oftrans-6-chloro-4-(2-fluorophenyl)-N-(2-propyl)-1,3-benzodioxan-2-carboxamidein 100 ml of anhydrous THF and 49 ml (49mmoles) of 1M (as BH₃) diboranein THF solution. The reaction mixture was hydrolyzed with 6N HCl andworked up as described previously. The hydrochloride salt of the aminewas formed in anhydrous ether; crystallization was slow and the mixturewas stored at 0° until separation was complete. The colorless crystals(2.54 g, 84% yield, mp 216°-218° (dec)), were recrystallized fromacetone. Recovery was 88% (2.23 g, mp 214.5°-216° (dec)).

Anal. Calc'd. for C₁₈ H₁₉ ClFNO₂.HCl: C, 58.07 H, 5.42; N, 3.76; Cl,19.05. Found: C, 58.12; H, 5.55; N, 3,79; Cl, 18.87.

EXAMPLE 8trans-4-(2-Fluorophenyl)-2-(2-propylaminomethyl)-1,3-benzodioxanhydrochloride

To a solution of 1.06 g (2.84 mmoles) oftrans-6-chloro-4-(2-fluorophenyl)-2-(2-propylaminomethyl)-1,3-benzodioxanhydrochloride in 200 ml of EtOH was added 0.79 ml (0.56 g, 5.68 mmoles)of triethylamine and 0.51 g of 10% Pd on carbon catalyst; the mixturewas hydrogenated at an initial gauge pressure of 3 atm. Hydrogen uptakewas initially rapid but slowed after ca. 10 min. After 2 hours, it wascomplete. The catalyst was filtered, the solvent was evaporated, and theresidue was partitioned between ether and dil. NaHCO₃ solution. Theether solution was washed with two portions of water, dried andevaporated.

The hydrochloride salt of the amine was formed in anhydrous ether.Crystallization from ether was slow. The salt was filtered andrecrystallized from acetone; colorless cyrstals, 0.715 g (74% yield); mp182°-183.5°.

Anal. Calc'd. for C₁₈ H₂₀ FNO₂.HCl: C, 63.99; H, 6.27; N, 4.15; Cl,10.50. Found: C, 63.87; H, 6.06; N, 3.98; Cl, 10.55.

EXAMPLE 9

General procedure for the preparation of compounds of the genericformula IV having the structure ##STR40##

Substitution in the procedure of examples 5a, 6a or 7a for the amineused therein of an equimolar amount of the appropriate amine producedthe compounds indicated in Table Ia and Ib below:

                                      Table Ia.                                   __________________________________________________________________________     ##STR41##                                                                                               cis or      Recrystallization                      Cmpd. No.                                                                            X    Y    NR.sub.1 R.sub.2                                                                        trans                                                                             m.p. ° C                                                                          Solvent*                            __________________________________________________________________________    1      Cl   H    NH.sub.2  cis 190.5-191.5 F                                  2      Cl   H    NH.sub.2  trans                                                                             201-202.5   K                                  3      Cl   4-Cl NH.sub.2  cis 199-200     F                                  4      Cl   2-F  NH.sub.2  cis 205-205.5   A,E                                5      NO.sub.2                                                                           H    NH.sub.2  cis 205-206     A,E                                6      Cl   H    NHMe      cis 169-170     F                                  7      Cl   H    NHMe      trans                                                                             177.5-179   K,L                                8      Cl   4-Cl NHMe      cis 195-196.5   F                                  9      Cl   2-F  NHMe      cis 184.5-186.5 B,E                                10     NO.sub.2                                                                           H    NHMe      cis 190-191     A                                  11     Cl   H    NHEt      cis 162-163     F                                  12     Cl   H    NHEt      trans                                                                             128-129     A,E                                13     Cl   H    NH-n-Pr   cis 136-137     F                                  14     Cl   H    NH-n-Pr   trans                                                                             109-110.5   A,E                                15     Cl   H    NH-iso-Pr cis 185-186     F                                  16     Cl   H    NH-iso-Pr trans                                                                             133.5-135   A,E                                17     Cl   4-Cl NH-iso-Pr cis 217-218     F                                  18     Cl   2-F  NH-iso-Pr cis 165-166     B                                                                 174-175.5   B,E                                19     Cl   2-F  NH-iso-Pr trans                                                                             125-126     A,E                                20     NO.sub.2                                                                           H    NH-iso-Pr cis 182.5-183.5 A,E                                21     Cl   H                                                                                   ##STR42##                                                                              cis 207.5-208   F                                  22     Cl   H                                                                                   ##STR43##                                                                              trans                                                                             174.5-177.5 A                                  23     Cl   H    NH-iso-Bu cis 157-158     F                                  24     Cl   H    NH-sec-Bu cis 190-191     F                                  25     Cl   H    NH-t-Bu   cis 174.5-175.5 F                                  26     Cl   H                                                                                   ##STR44##                                                                              cis 194.5 -195.5                                                                              F                                  27     Cl   H                                                                                   ##STR45##                                                                              cis 181-183     F                                  28     Cl   H                                                                                   ##STR46##                                                                              cis 192-193.5   F                                  29     Cl   H    NMe.sub.2 cis 220-221     F                                  30     Cl   H    NMe.sub.2 trans                                                                             --          --                                 31     Cl   2-F  NMe.sub.2 cis 192-194     A,E                                32     NO.sub.2                                                                           H    NMe.sub.2 cis 169-170     A,E                                33     Cl   H    NEt.sub.2 cis 188.5-190   F                                  34     Cl   H    NEt.sub.2 trans                                                                             82-85       B,E                                35     Cl   H                                                                                   ##STR47##                                                                              cis 234.5-235   F                                  36     Cl   H                                                                                   ##STR48##                                                                              trans                                                                             137-138.5   B,E                                37     Cl   H                                                                                   ##STR49##                                                                              cis 174-175.5   F                                  38     Cl   H                                                                                   ##STR50##                                                                              cis 174-175     F                                  39     Cl   N                                                                                   ##STR51##                                                                              trans                                                                             174.5-177.5 M                                  40     Cl   H                                                                                   ##STR52##                                                                              cis 173-174.5   F                                  41     Cl   H                                                                                   ##STR53##                                                                              cis 216-217.5   F                                  __________________________________________________________________________     *A, 95% EtOH; B, MeOH; C, acetone; D, ether; E, water; F, absolute EtOH;      G, Skellysolve B (essentially n-hexane), H, acetonitrile; I, isopropyl        alcohol; K, CHCl.sub.3 ; L, CCl.sub.4 ; M, nitromethane.                 

                  Table Ib.                                                       ______________________________________                                        Analysis                                                                      Cmpd.  Calcd            Found                                                 No.    C        H       N     C      H     N                                  ______________________________________                                        1      62.18    4.18    4.84  61.84  4.21  4.90                               2      62.19    4.18    4.83  61.99  4.43  4.86                               3      55.57    3.42    4.32  55.30  3.52  4.34                               4      58.55    3.60    4.55  58.58  3.64  4.65                               5      60.00    4.03    9.33  59.93  4.14  9.39                               6      63.27    4.64    4.61  63.30  4.72  4.63                               7      63.27    4.64    4.61  63.16  4.64  4.56                               8      56.83    3.87    4.14  56.80  4.03  4.25                               9      59.73    4.07    4.35  59.73  4.26  4.44                               10     61.14    4.49    8.91  61.14  4.53  8.76                               11     64.25    5.06    4.41  63.81  5.19  4.33                               12     64.25    5.07    4.41  64.49  5.19  4.37                               13     65.16    5.47    4.22  64.84  5.53  4.24                               14     65.16    5.47    4.22  64.82  5.67  4.19                               15     65.16    5.47    4.22  65.02  5.50  4.29                               16     65.16    5.47    4.22  65.12  5.66  4.25                               17     59.03    4.68    3.82  59.29  4.88  3.98                               18     61.80    4.90    4.01  61.91  5.13  4.06                               19     61.80    4.90    4.01  61.83  5.20  4.05                               20     63.15    5.30    8.18  62.99  5.48  8.23                               21     65.55    4.89    4.25  65.34  5.02  4.25                               22     65.55    4.89    4.25  65.12  5.04  4.27                               23     65.98    5.83    4.05  65.60  5.86  4.09                               24     65.98    5.83    4.05  65.76  5.70  4.02                               25     65.98    5.83    4.05  65.69  5.83  3.79                               26     66.37    5.28    4.08  66.42  5.38  3.99                               27     67.13    5.63    3.92  66.95  5.70  3.96                               28     67.82    5.96    3.77  67.77  5.96  3.63                               29     65.07    5.14    4.46  65.11  4.99  4.98                               30     64.26    5.08    4.41  64.11  5.05  4.48                               31     60.81    4.50    4.17  60.94  4.53  4.20                               32     62.19    4.91    8.53  61.97  5.07  8.42                               33     65.98    5.83    4.05  65.73  5.95  3.77                               34     65.98    5.83    4.05  65.87  5.89  3.87                               35     66.37    5.28    4.08  66.37  5.27  4.04                               36     66.37    5.28    4.08  66.45  5.39  3.86                               37     67.13    5.63    3.92  67.27  5.66  3.91                               38     63.42    5.04    3.89  63.12  5.15  3.96                               39     63.42    5.04    3.89  63.48  5.24  4.09                               40     64.42    5.68    7.52  64.57  5.58  7.34                               41     63.53    5.33    3.37  63.45  5.29  3.36                               ______________________________________                                    

EXAMPLE 10

General procedure for the preparation of compounds of the genericformula IV having the structure ##STR54##

Substitution in the procedure of examples 5b, 6b or 7b for the amineused therein of an equimolar amount of the appropriate amine producedthe compounds indicated in Tables IIa and IIb below:

                                      Table IIa                                   __________________________________________________________________________     ##STR55##                                                                    Cmpd.                cis or                                                                            m.p.  Recrystallization                              No. X  Y  NR.sub.1 R.sub.2                                                                         trans                                                                             ° C                                                                          Solvent*                                       __________________________________________________________________________     1B Cl H  NH.sub.2   cis 203-204.5                                                                           B,D                                             2B Cl H  NH.sub.2   trans                                                                             212.5-213.5                                                                         D                                                                       (dec)                                                 3B H  H  NH.sub.2   cis 215-218.5                                                                           F,G                                                                     228.5-230                                                                           F                                               4B H  H  NH.sub.2   trans                                                                             182.5-183                                                                           C                                                                       (dec)                                                 5B Cl 4-Cl                                                                             NH.sub.2   cis 254-256                                                                             F,G                                             6B Cl 2-F                                                                              NH.sub.2   cis 219-219.5                                                                           C                                                                       (dec)                                                 7B NO.sub.2                                                                         H  NH.sub.2   cis 197-198                                                                             B,D                                                                     (dec)                                                 8B Cl H  NHMe       cis 242.5-243                                                                           D,F                                             9B Cl H  NHMe       trans                                                                             234.5-235                                                                           B,D                                                                     (dec)                                                10B H  H  NHMe       cis 226.5-227                                                                           D,F                                            11B H  H  NHMe       trans                                                                             185-187.5                                                                           B,D                                            12B Cl 4-Cl                                                                             NHMe       cis 241.5-242.5                                                                         F                                              13B Cl 2-F                                                                              NHMe       cis 247-248                                                                             B,D                                                                     (dec)                                                14B NO.sub.2                                                                         H  NHMe       cis 249-250                                                                             B,D                                                                     (dec)                                                15B Cl H  NHEt       cis 234-235                                                                             F                                              16B Cl H  NHEt       trans                                                                             249-250                                                                             B                                                                       (dec)                                                17B H  H  NHEt       cis 214-215.5                                                                           F                                              18B H  H  NHEt       trans                                                                             217-217.5                                                                           B,D                                                                     (dec)                                                19B Cl H  NH-n-Pr    cis 227-228                                                                             F,G                                                                     (dec)                                                20B Cl H  NH-n-Pr    trans                                                                             237-239                                                                             B,D                                                                     (dec)                                                21B H  H  NH-n-Pr    trans                                                                             178-179.5                                                                           C                                              22B Cl H  NH-iso-Pr  cis 226-227                                                                             F                                              23B Cl H  NH-iso-Pr  trans                                                                             230-231                                                                             B,D                                                                     (dec)                                                24B H  H  NH-iso-Pr  cis 203.5-204                                                                           C                                              25B H  H  NH-iso-Pr  trans                                                                             200.5-201                                                                           C                                                                       (dec)                                                26B Cl 4-Cl                                                                             NH-iso-Pr  cis 234-235                                                                             F,D                                            27B Cl 2-F                                                                              NH-iso-Pr  cis 203-204                                                                             C                                              28B Cl 2-F                                                                              NH-iso-Pr  trans                                                                             214.5-216                                                                           C                                                                       (dec)                                                29B H  2-F                                                                              NH-iso-Pr  trans                                                                             182-183.5                                                                           C                                              30B NO.sub.2                                                                         H  NH-iso-Pr  cis 172-174.5                                                                           H                                                                       (dec)                                                31B Cl H                                                                                 ##STR56## cis 210-211                                                                             F                                              32B Cl H                                                                                 ##STR57## trans                                                                             222-226.5  (dec)                                                                    B                                              33B H  H                                                                                 ##STR58## trans                                                                             205-206 (dec)                                                                       B,D                                            34B Cl H  NH-iso-Bu  cis 166-167.5                                                                           F,D                                            35B Cl H  NH-sec-Bu  cis 205-206                                                                             C                                              36B Cl H  NH-t-Bu    cis 219-219.5                                                                           H                                              37B Cl H                                                                                 ##STR59## cis 176-177                                                                             F                                              38B Cl H                                                                                 ##STR60## cis 242-243.5                                                                           F                                              39B Cl H                                                                                 ##STR61## cis 220-221.5                                                                           --                                             40B Cl H                                                                                 ##STR62## cis 185.187.5                                                                           F,D                                            41B Cl H  NMe.sub.2  cis 217.5- 219                                                                          B,D                                            42B Cl H  NMe.sub.2  trans                                                                             167.5-169.5                                                                         H,D                                            43B Cl 4-Cl                                                                             NMe.sub.2  cis 233-234                                                                             H                                              44B Cl 2-F                                                                              NMe.sub.2  cis 192-194                                                                             C                                              45B Cl H                                                                                 ##STR63## cis 158-160                                                                             F                                              46B Cl H  NMeEt      trans                                                                             144-147.5                                                                           C                                              47B Cl H  NEt.sub.2  cis 143.5-145                                                                           F,G                                            48B Cl H  NEt.sub.2  trans                                                                             foam  B,D                                                                     95-125                                               49B Cl H                                                                                 ##STR64## cis 169-171                                                                             F,D                                            50B Cl H                                                                                 ##STR65## trans                                                                             241.5-242 (dec)                                                                     B,D                                            51B Cl H                                                                                 ##STR66## cis 234.5-235                                                                           F,G                                            52B H  H                                                                                 ##STR67## cis 290.5-210.5                                                                         F,G                                            53B Cl H                                                                                 ##STR68## cis 210-212.5                                                                           F,D                                            54B Cl H                                                                                 ##STR69## cis 207-209                                                                             F                                              55B Cl H                                                                                 ##STR70## cis 219-220                                                                             I                                              __________________________________________________________________________     *A, 95% EtOH; B, MeOH; C, acetone; D, ether; E, water; F, absolute EtOH;      G, Skellysolve B; (essentially n-hexane) H, acetonitrile; I, isopropyl        alcohol; K, CHCl.sub.3 ; L, CCl.sub.4 ; M, nitromethane.                 

                  Table IIb.                                                      ______________________________________                                        Anal.                                                                         Cmpd.  Calcd            Found                                                 No.    C        H       N     C      H     N                                  ______________________________________                                         1B    57.71    4.84    4.49  57.60  4.94  4.31                                2B    57.71    4.84    4.49  57.77  4.87  4.51                                3B    64.86    5.80    5.04  64.86  5.74  5.03                                4B    64.86    5.81    5.04  65.06  5.90  5.06                                5B    51.97    3.96    3.93  51.87  4.05  4.00                                6B    54.56    4.27    4.24  54.25  4.20  4.17                                7B    55.82    4.68    8.68  56.05  4.92  8.77                                8B    58.91    5.25    4.29  58.94  5.34  4.09                                9B    58.91    5.25    4.29  59.06  5.16  4.44                               10B    65.86    6.22    4.80  65.79  6.20  4.56                               11B    65.86    6.22    4.80  66.06  6.03  4.69                               12B    53.28    4.47    3.88  53.37  4.60  3.77                               13B    55.83    4.69    4.07  56.01  4.90  4.08                               14B    57.06    5.09    8.32  57.23  5.28  8.35                               15B    60.01    5.63    4.12  60.10  5.86  3.94                               16B    60.01    5.63    4.12  59.87  5.68  4.27                               17B    66.76    6.59    4.58  66.46  6.73  4.60                               18B    66.77    6.59    4.58  66.55  6.65  4.42                               19B    61.02    5.98    3.95  60.81  5.92  4.00                               20B    61.02    5.98    3.95  60.88  6.01  3.75                               21B    67.59    6.93    4.38  67.52  6.94  4.39                               22B    61.02    5.98    3.95  60.97  6.08  4.00                               23B    61.02    5.98    3.95  60.68  6.01  3.90                               24B    67.59    6.93    4.38  67.26  6.96  4.40                               25B    67.59    6.93    4.38  67.70  6.92  4.33                               26B    55.62    5.19    3.60  55.83  5.35  3.64                               27B    58.07    5.42    3.76  58.23  5.59  3.73                               28B    58.07    5.42    3.76  58.12  5.55  3.79                               29B    63.99    6.27    4.15  63.87  6.06  3.98                               30B    59.25    5.80    7.68  59.16  6.04  7.77                               31B    61.37    5.43    3.98  60.99  5.43  3.92                               32B    61.37    5.44    3.98  61.40  5.40  3.89                               33B    68.02    6.34    4.41  67.76  6.46  4.18                               34B    61.96    6.29    3.80  61.62  6.27  3.72                               35B    61.96    6.29    3.80  61.87  6.30  3.77                               36B    61.96    6.29    3.80  61.80  6.35  3.86                               37B    66.37    5.28    4.08  66.19  5.36  4.15                               38B    62.30    5.78    3.82  62.45  5.79  4.11                               39B    63.15    6.10    3.68  63.21  6.10  3.52                               40B    63.96    6.39    3.55  63.74  6.34  3.51                               41B    60.01    5.63    4.12  60.06  5.75  4.15                               42B    60.01    5.63    4.12  60.07  5.63  4.21                               43B    54.49    4.84    3.74  54.20  4.84  3.92                               44B    56.99    5.06    3.91  56.88  5.12  3.85                               45B    58.11    5.72    3.78  57.98  5.66  3.62                               46B    61.02    5.98    3.95  60.89  5.98  3.92                               47B    61.96    6.29    3.80  62.14  6.16  4.01                               48B    61.96    6.29    3.80  62.11  6.33  3.66                               49B    62.30    5.78    3.83  62.39  6.12  3.57                               50B    62.30    5.78    3.83  62.36  5.85  3.84                               51B    63.14    6.09    3.68  62.86  6.17  3.43                               52B    69.45    6.99    4.05  69.27  7.11  4.05                               53B    59.69    5.54    3.66  59.41  5.53  3.58                               54B    55.63    5.84    6.49  55.94  5.71  6.48                               55B    60.28    5.75    3.20  60.03  5.82  3.32                               ______________________________________                                    

All temperatures reported herein are in degrees centrigrade (° C).

EXAMPLE 11 A.trans-6-Chloro-4-phenyl-N-(3-dimethylaminopropyl)-1,3-benzodioxan-2-carboxamidehydrochloride (BL-4932A)

trans-6-Chloro-4-phenyl-1,3-benzodioxan-2-carboxylic acid (2.91 g., 10mmoles), thionyl chloride (10 ml) and dry DMF (3drops) were added to dryCH₂ Cl₂ (100 ml) and heated at reflux for 2 hrs. The solvent and excessthionyl chloride were removed under reduced pressure with the aid ofadded benzene. The remaining oily acid chloride was redissolved in dryCH₂ Cl₂ (50 ml) and dimethylaminopropyl amine (1.02 g., 10 mmoles) wasadded with stirring (exothermic). Stirring at 22° under an atmosphere ofdry N₂ was carried out for 221/2 hrs, followed by refluxing for 30 mins.Solvent removal afforded a foam which was triturated with Et₂ O/EtOAc togive a white solid. Recrystallization from isopropyl alcohol gave whitecrystals (2.55 g., 62.1%, mp 188°-191.5° d). Spectra (ir, nmr) wereconsistent with the structure; mass spec M ⁺ = 375.

Anal. calc'd. for C₂₀ H₂₃ CIN₂ O₃.HCL: C, 58.40;

H, 5.88; N, 6.81.

(Corrected for 2.4% H₂ O) Found: C, 58.38; H, 5,91; N,

7.61.

B.trans-6-chloro-4-phenyl-2-[N-(3-dimethylaminopropyl)aminomethyl]-1,3-benzodioxanhydrochloride

Substitution in the procedure of example 5b for thecis-6-chloro-N-methyl-4-phenyl-1,3-benzodioxan-2-carboxamide usedtherein of an equimolar quantity of BL-4932A produces the titlecompound.

EXAMPLE 12 A.trans-4-Phenyl-N-(3-dimethylaminopropyl)-1,3-benzodioxan-2-carboxamidehydrochloride (BL-5028A)

trans-6-Chloro-4-phenyl-N-(3-dimethylaminopropyl)1,3-benzodioxan-2-carboxamidehydrochloride (1.0 g., 2.43 mmole) was mixed with triethylamine (0.526g., 5.2 mmole) and 30% Pd on Celite catalyst (0.3 g.,) in 200 ml ofabsolute EtOH and hydrogenated in a Parr apparatus for 30 mins. at aninitial H₂ pressure of 48 psi. The uptake was 13 lbs. of H₂ and aftercatalyst removal, the filtrate was stripped of solvent under reducedpressure. The residue was partitioned between CH₂ Cl₂ and 2% Na₂ CO₃solution. After extraction of the aqueous with a second portion of CH₂Cl₂, the organics were combined, washed with H₂ O, dried (MgSO₄) andstripped to a syrup under reduced pressure. The .HCL salt was formed inCH₂ Cl₂ in the usual manner, and after solvent removal, crystallizationwas effected by trituration in hot EtOAc, followed by cooling (0.66 g.,72%). Recrystallization from EtOAc-abs EtOH gave analytical material (mp165°-170° d).

Anal. calc'd. for C₂₀ H₂₄ N₂ O₃.HCl: C, 63.74

H. 6.69; N, 7.43; Cl, 9.41.

Found: C, 64.09; H, 6.71; N, 7.32; Cl, 9.62.

B.trans-4-Phenyl-2-[N-(3-dimethylaminopropyl)-aminomethyl]-1,3-benzodioxanhydrochloride

Substitution in the procedure of example 5b for thecis-6-chloro-N-methyl-4-phenyl-1,3-benzodioxan-2-carboxamide usedtherein of an equimolar quantity of BL-5028A produces the titlecompound.

EXAMPLE 13 A.cis-6-Chloro-4-phenyl-N-(3-dimethylaminopropyl)1,3-benzodioxan-2-carboxamidehydrochloride (BL-4971A)

cis-6-Chloro-4-phenyl-1,3-benzodioxan-2-carboxylic acid (2.91 g., 10mmoles), ethionyl chloride (10 ml) and dry DMF (4 drops) were refluxedin 100 ml of dry CH₂ Cl₂ for 2 hrs. Removal of solvent and excessreagent under reduced pressure afforded the crude acid chloride whichwas then redissolved in CH₂ Cl₂ (50 ml) and treated withdimethylaminopropyl amine (1.53 g., 15 mmloes). The reaction wassomewhat exothermic and the stirred mixture was maintained at 20° for 35mins., and then at reflux for 45 mins. After solvent removal, theresidue was partitioned between 5% Na₂ CO₃ solution and CH₂ Cl₂ (2portions). The organics were then washed with brine, dried (MgSO₄) andtreated with HClg. Solvent removal and crystallization of the residuefrom isopropyl alcohol gave the product as a white solid (3.34 g.,81.3%). Recrystallization from abs EtOH:Et₂ O afforded pure material (mp213° -216° d).

Anal. calc'd. for C₂₀ H₂₃ ClN₂ O₃.HCl: C, 58.40;

H, 5.88; N, 6.81.

Found: C, 58.83; H, 5.85; N, 6.81.

B.cis-6-Chloro-4-phenyl-2-[N-(3-dimethylaminopropyl)aminomethyl]-1,3-benzodioxanhydrochloride

Substitution in the procedure of example 5b for thecis-6-chloro-N-methyl-4-phenyl-1,3-benzodioxan-2-carboxamide usedtherein of an equimolar quantity of BL-4971A produces the titlecompound.

EXAMPLE 14 A.cis-4-Phenyl-N-(3-dimethylaminopropyl)-1,3-benzodioxan-2-carboxamidehydrochloride (BL-4981A)

cis-6-Chloro-4-phenyl-N-(3-dimethylaminopropyl)-1,3-benzodioxan-2-carboxamidehydrochloride (1.06 g, 2.59 mmole), triethylamine (0.526 g., 5.2 mmole)and 30% Pd on Celite (0.6 g) were mixed in abs EtOH (200 ml) andhydrogenated in a Parr apparatus for 21/2 hrs. (14 lb H₂ uptake). Workupand treatment with HClg in the usual manner (see example 12) gave theproduct (0.7 g., 71.8% mp 178°-186° d) after recrystallization fromi-PrOH:Et₂ O.

Anal. calc'd. for C₂₀ H₂₄ N₂ O₃.HCl: C, 63.74; H,

6.69; N, 7.43; Cl, 9.41.

(Corrected for 0.29% H₂ O) Found: C, 63.48; H, 6.61; N,

7.16; Cl, 9.28.

B.cis-4-Phenyl-2-[N-(3-dimethylaminopropyl)-aminomethyl]-1,3-benzodioxanhydrochloride

Substitution in the procedure of example 5b for thecis-6-chloro-N-methyl-4-phenyl-1,3-benzodioxan-2-carboxamide usedtherein of an equimolar quantity of BL-4981A produces the titlecompound.

EXAMPLE 15trans-6-Chloro-4-phenyl-N-(3-piperidinopropyl)-1,3-benzodioxan-2-carboxamidehydrochloride

Substitution in the procedure of example 11 for thedimethylaminopropylamine used therein of an equimolar quantity of3-piperidinopropylamine produces the title compound.

EXAMPLE 16trans-4-Phenyl-N-(2-morpholinoethyl)-1,3-benzodioxan-2-carboxamidehydrochloride

Substitution in the procedure of example 11 for thedimethylaminopropylamine used therein of an equimolar quantity of2-morpholinoethylamine produces the title product.

EXAMPLE 17cis-6-Chloro-4-phenyl-N-(4-methylaminobutyl)-1,3-benzodioxan-2-carboxamidehydrochloride

Substitution in the procedure of example 11 for theN,N-dimethylaminopropylamine used therein of an equimolar quantity ofN-methylaminobutylamine produces the title compound.

EXAMPLE 18cis-4-Phenyl-N-(2-diethylaminoethyl)-1,3-benzodioxan-2-carboxamidehydrochloride

Substitution in the procedure of example 11 for theN,N-dimethylaminopropylamine used therein of an equimolar quantity ofN,N-diethylaminoethylamine produces the title product.

We claim:
 1. The compound having the formula ##STR71## in which X and Yare alike or different and are H, F, Cl, Br, CF₃ or Nitro, Z is aradical having the formula ##STR72## in which R⁶ is H, (lower) alkyl orphenyl, R¹ and R² are alike or different and each is H, lower alkyl,cycloloweralkyl or when taken together with the nitrogen a heterocyclicring having the formula ##STR73## and n is an integer of 1 to 4inclusive; or a pharmaceutically acceptable acid addition salt thereof.2. The compound of claim 1 having the formula ##STR74## in which X and Yare alike or different and are H, F, Cl, Br, CF₃ or nitro, Z is aradical having the formula ##STR75## in which R⁶ is H, (lower) alkyl orphenyl, R¹ and R² are alike or different and each is H, lower alkyl,cycloloweralkyl or when taken together with the nitrogen a heterocyclicring having the formula ##STR76## and n is an integer of 1 to 4inclusive; or a pharmaceutically acceptable acid addition salt thereof.3. The compound of claim 1 having the formula ##STR77## in which X and Yare alike or different and are H, F, Cl, Br, CF₃ or NO₂, and Z is aradical having the formula ##STR78## in which R⁶ is H, (lower) alkyl orphenyl, R¹ and R² are alike or different and each is H, lower alkyl,cycloloweralkyl or when taken together with the nitrogen a heterocyclicring having the formula ##STR79## and n is an integer of 1 to 4inclusive; or a pharmaceutically acceptable acid addition salt thereof.4. The compound of claim 1 having the formula ##STR80## or thehydrochloride salt thereof.
 5. The compound of claim 1 having theformula ##STR81## or the hydrochloride salt thereof.
 6. The compound ofclaim 1 having the formula ##STR82## or the hydrochloride salt thereof.7. The compound of claim 1 having the formula ##STR83## or apharmaceutically acceptable acid addition salt thereof.
 8. The compoundof claim 1 having the formula ##STR84## or a pharmaceutically acceptableacid addition salt thereof.
 9. The compound of claim 1 having theformula ##STR85## or a pharmaceutically acceptable acid addition saltthereof.
 10. The compound of claim 1 having the formula ##STR86## or apharmaceutically acceptable acid addition salt thereof.
 11. The cisisomer of the compound of claim
 7. 12. The cis isomer of the compound ofclaim
 8. 13. The cis isomer of the compound of claim
 9. 14. The cisisomer of the compound of claim
 10. 15. The compound of claim 1 havingthe formula ##STR87## or the hydrochloride salt thereof.
 16. Thecompound of claim 1 having the formula ##STR88## or the hydrochloridesalt thereof.
 17. The trans isomer of the compound of claim
 7. 18. Thetrans isomer of the compound of claim
 8. 19. The trans isomer of thecompound of claim
 9. 20. The trans isomer of the compound of claim 10.